Regional cerebral blood flow (rCBF) studies of major depression have yielded variable results. The present study employed a longitudinal observation method to measure rCBF every 3 months during treatment. Thirteen patients with major depressive disorder underwent single-photon emission computed tomography (SPECT) with 99mTc-HMPAO three times over a 6-month period. rCBF was analyzed with the Statistical Parametric Mapping. The findings were compared to scans from 14 normal control subjects. Depression symptoms were rated using the Hamilton Rating Scale for Depression. At baseline, the main regions with lower rCBF compared to controls were the middle and inferior frontal gyri, superior temporal gyrus, and cingulate cortex. Three months later, despite significant improvement of depressive symptoms, decreased rCBF was observed in the same regions, but to lesser extent. At 6 months, depressive symptoms showed continued improvement, and rCBF in the superior temporal gyrus increased up to control levels, but rCBF in the temporal pole, cingulate, and inferior frontal gyrus remained low. The results of the present study suggest that there might be time- and state-dependent differences in rCBF recovery in patients with major depression.
Altered brain activity in patients with mood disorders can be reflected in changes in regional cerebral blood flow (rCBF). Many studies have reported rCBF measured by single-photon emission computed tomography (SPECT) in patients with major depression, but comparisons of rCBF with healthy controls and during the course of treatment are inconsistent [
The present study was conducted to solve the problem of inconsistent results in imaging studies. We prospectively followed patients during their treatment course for 6 months and measured rCBF (as a ratio to blood flow in the cerebellum) using SPECT every 3 months. To our knowledge, there have been no reports of serial rCBF measurements performed over 6 months. Our goal was to delineate altered brain function in patients with major depression during exacerbation periods and the alleviation of depressive symptoms following pharmacological treatment.
Subjects were patients with depression who fulfilled the diagnostic criteria for a major depressive episode in the Diagnostic and Statistical Manual of Mental Disorders, 4th edition [
SPECT was used in rCBF distribution measurements, with 99mTc-HMPAO (hexamethylpropyleneamineoxime) 1110 MBq as a radioactive agent given in an intravenous bolus injection via a line secured in the median antebrachial vein. Before and after the injection, the subjects rested in a quiet room with the lights dimmed while wearing an eye mask and ear plugs. Imaging was performed 40 min after injection. Because depressive symptoms such as psychomotor retardation in major depression patients show considerable diurnal variation, 99mTc- HMPAO injection was given between 10 and 11 a.m. SPECT imaging was performed three times, during the depressive phase before treatment (baseline) and 3 and 6 months later. Depressive symptoms were evaluated with the 24-item HRSD within 4 days of each SPECT study.
A Shimadzu Headtome 030 (ring type, HR collimator) was used in SPECT imaging, and image slices were parallel to the orbitomeatal base line (OM line). The obtained images were 64 × 64 pixels, and slice thickness was approximately 13 mm.
123I and 99mTc are the most commonly used isotopes for imaging cerebral blood flow with SPECT. Absolute cerebral blood flow can be calculated by collecting arterial blood when using 123I; however, this is not possible when using 99mTc. We calculated rCBF as a relative value based on the cerebellum as the reference region because cerebellar blood flow is not considered to be affected by factors such as age [
As a reference site for each imaging, the mean count for the entire cerebellum including the vermis on slices that contained the lower-central pons was calculated, and the value obtained through each pixel count divided by this value was defined as the ratio to the cerebellum used in the analysis.
Nine slices were imaged, but the data were rearranged to form 20 slices with resampling (3-dimensional linear method) and expanded (normalized) to a standard brain. They were then compared voxel by voxel using SPM-99 (Statistical Parametric Mapping 99). The significance levels for the intra- and intergroup comparisons were set as p < 0.005 and p < 0.001, respectively.
Measurements at baseline, 3 months, and 6 months were compared in the subject group using paired t-tests (p < 0.005), and between-group comparisons with the healthy control group were performed with two-sample t-tests (p < 0.001). The cluster size threshold was set to greater than 40 voxels for the intra- and intergroup comparisons. Image processing was performed with Medex 3.3 (Sensor Systems, Inc.). From this analysis with SPM-99, the anatomical positions of each cluster and Brodmann area were identified using the Talairach atlas [
The analyses of other variables such as age, education, and HRSD were conducted using t-tests.
A total of 13 patients (9 female, 4 male) who met the criteria were enrolled. They had a mean age of 46 ± 13 (22 - 62) years and 11.5 ± 1.7 years of education. The control group consisted of 14 subjects (7 female, 7 male) with a mean age of 31.5 ± 12.8 years and had 15.4 ± 3.0 years of education. The control group was thus significantly younger (t (24.31) = 2.952, p = 0.007) and had significantly more years of education (t (20.48) = 4.099, p < 0.01). Depressive symptoms in terms of HRSD scores were 31.5 ± 12.0 at baseline, 11.0 ± 4.3 at 3 months, and 6.2 ± 2.7 at 6 months. The mean score had decreased by 65% or more at second and third measurements, and these differences were significant (baseline vs. 3 months, t (12) = 6.187, p < 0.01; baseline vs. 6 months, t (12) = 8.415, p < 0.01).
Case no. | Imipramine equivalent (mg) | Chlorpromazine equivalent (mg) | Diazepam equivalent (mg) | ||||||
---|---|---|---|---|---|---|---|---|---|
0 m | 3 m | 6 m | 0 m | 3 m | 6 m | 0 m | 3 m | 6 m | |
1 | 50 | 50 | 50 | 0 | 0 | 0 | 25 | 14 | 14 |
2 | 50 | 75 | 75 | 0 | 0 | 0 | 5 | 5 | 5 |
3 | 250 | 245 | 150 | 0 | 0 | 0 | 30 | 16 | 8 |
4 | 30 | 30 | 30 | 0 | 0 | 0 | 10 | 15 | 15 |
5 | 90 | 33 | 33 | 110 | 70 | 70 | 5 | 13 | 8 |
6 | 125 | 225 | 225 | 50 | 60 | 138 | 11 | 11 | 7 |
7 | 10 | 10 | 10 | 15 | 30 | 50 | 6 | 6 | 6 |
8 | 10 | 15 | 15 | 0 | 26 | 300 | 5 | 17 | 2 |
9 | 40 | 150 | 125 | 0 | 130 | 160 | 4 | 4 | 4 |
10 | 50 | 100 | 75 | 0 | 0 | 0 | 18 | 10 | 10 |
11 | 45 | 65 | 45 | 0 | 0 | 0 | 0 | 0 | 0 |
12 | 0 | 0 | 0 | 50 | 0 | 0 | 3 | 2 | 2 |
13 | 13 | 125 | 125 | 0 | 0 | 0 | 5 | 5 | 5 |
Avg | 59.4 | 89.4 | 75.7 | 18.7 | 26.3 | 59.8 | 8.5 | 8.7 | 6 |
Std | 69.9 | 82.6 | 68.3 | 34.5 | 41.2 | 94.9 | 8.2 | 5.8 | 4 |
a. The doses (mg/day) of antidepressants, antipsychotics, and antianxiety medications are expressed in imipramine, chlorpromazine, and diazepam equivalents, respectively. Equivalents were calculated based on the conversion table formulated by the clinical psycho-pharmacology study group of Keio University [
shows the antidepressant, antipsychotic, and antianxiety drug amounts in equivalent dosages of imipramine, chlorpromazine, and diazepam, respectively, that were taken by patients at each time point. The conversion in equivalent dosages of imipramine, chlorpromazine, and diazepam was calculated based upon the conversion table formulated by clinical psycho-pharmacology study group of Keio University [
The regions where rCBF differences were seen in patients compared to the control group are listed in
The lower rCBF areas improved at 3 and 6 months, particularly in the lateral prefrontal cortices and cingulate gyrus. After 3 months, there were no longer differences in rCBF between the two groups in the right inferior frontal gyrus (orbitofrontal area), left middle frontal gyrus, left anterior cingulate (antero-inferior), or left middle and superior frontal gyri (
After 6 months, the lower rCBF areas of patients with depression were no longer significant compared to controls in the right inferior frontal gyrus (orbitofrontal area), right superior temporal gyrus (temporal pole), bilateral middle frontal gyri, anterior cingulate (antero-inferior), and middle and superior frontal gyri (
As there was a significant difference in mean age between the patient and control groups, we attempted to recruit an additional control group whose age corresponded to those of the patients; however, the Headtome γ-camera used in this study was unavailable during new data collection due to unforeseen circumstances. Therefore, we were unable to gather data from this older control group. To compensate the failed attempt to add control subjects, we examined the effect of age on rCBF in five representative regions of interest (ROIs: cingulate, caudate, putamen, thalamus, and dorsolateral prefrontal cortex [DLPFC]) in patients at baseline by assessing the correlation between age and bilateral rCBF. The Pearson correlation coefficient was 0.068 (p = 0.442), indicating no correlation between age and rCBF in our patient group.
Comparison | Brain region | Left or right | Brodmann area | Z score |
---|---|---|---|---|
0 months < control | Middle & superior frontal gyri | Left | 10 | 4.68 |
Middle frontal gyrus | Right | 10, 46 | 4.57 | |
Middle frontal gyrus | Left | 11 | 5.02 | |
Inferior frontal gyrus (orbitofrontal area) | Right | 47 | 5.02 | |
Inferior frontal gyrus | Right | 44 | 4.70 | |
Cingulate (frontal portion) | Both | 32 | 5.10 | |
Cingulate (antero-inferior) | Left | 32 | 4.99 | |
Superior temporal gyrus (temporal pole) | Left | 38 | 5.79 | |
Superior temporal gyrus (temporal pole) | Right | 38 | 4.42 | |
3 months < control | Middle frontal gyrus | Right | 10, 9 | 4.21 |
Inferior frontal gyrus | Right | 47 | 4.6 | |
Cingulate (frontal portion) | Both | 32 | 4.14 | |
Superior temporal gyrus (temporal pole) | Left | 38 | 5.31 | |
Superior temporal gyrus (temporal pole) | Right | 38 | 4.25 | |
6 months < control | Inferior frontal gyrus | Right | 47 | 4.22 |
Cingulate (frontal portion) | Both | 32 | 4.33 | |
Superior temporal gyrus (temporal pole) | Left | 38 | 5.48 | |
0 months > control | n. d. | |||
3 months > control | Parahippocampal gyrus | Right | 27 | 3.95 |
Middle temporal gyrus | Left | 21 | 4.46 | |
Superior temporal gyrus | Both | 22, | 5.04 | |
Inferior temporal gyrus | Right | 37 | 3.92 | |
Fusiform gyrus | Both | 37 | 4.37 | |
Middle occipital gyrus | Left | 19, 37 | 4.44 | |
Lingual gyrus | Right | 18 | 4.37 | |
Cuneus | Right | 17, 18 | 3.75 | |
6 months > control | Middle temporal gyrus | Right | 21 | 4.92 |
Superior temporal gyrus | Left | 22 | 4.14 | |
Fusiform gyrus | Both | 37 | 4.12 | |
Middle occipital gyrus | Both | 19 | 5.18 | |
Lingual gyrus | Both | 18 | 4.60 | |
Cuneus | Both | 17, 18 | 4.60 |
a. The regions with significant differences in blood flow between the depression and control groups for 0 (baseline), 3, and 6 months after treatment initiation are listed. Z scores represent the biggest differences in blood flow across voxels within the region. n.d.: not detected.
Anatomical locations and Brodmann areas that changed over time among the subjects in the depression group are shown in
Comparison | Brain region | Left or right | Brodmann area | Z score |
---|---|---|---|---|
3 months > 0 months | Middle frontal gyrus | Left | 10 | 3.30 |
Superior frontal gyrus | Left | 9 | 2.75 | |
Middle temporal gyrus | Left | 21 | 3.21 | |
Precentral gyrus | Left | 4 | 3.82 | |
3 months < 0 months | Orbitofrontal gyrus | Right | 11 | 3.16 |
Sub-lobar insula | Right | 13 | 3.46 | |
Superior temporal gyrus (mid portion) | Right | 22 | 3.89 | |
Superior temporal gyrus (posterior) | Left | 22 | 3.40 | |
Superior temporal gyrus (anterior) | Right | 22 | 3.26 | |
Precentral gyrus | Right | 4 | 3.19 | |
6 months > 3 months | Superior frontal gyrus | Right | 10 | 3.34 |
Middle frontal gyrus | Right | 46 | 3.15 | |
Cingulate (frontal portion) | Left | 32 | 2.95 | |
Precuneus | Left | 7 | 3.41 | |
Fusiform gyrus | Left | 37 | 3.20 | |
Lingual gyrus | Left | 18, 19 | 3.20 | |
Cuneus | Left | 17, 18 | 3.30 | |
6 months < 3 months | Inferior frontal gyrus, | Left | 47, | 3.60 |
Superior temporal gyrus (temporal pole) | Left | 38 | 3.60 | |
Middle temporal gyrus | Left | 21 | 3.10 | |
Superior temporal gyrus (posterior) | Right | 22 | 3.38 |
a. The regions with significant changes in blood flow between 0 (baseline) and 3 months and 3 and 6 months after treatment initiation are listed. Z scores represent the biggest changes in blood flow across voxels within the region.
We found that rCBF values in the superior temporal gyrus (temporal pole), cingulate (frontal portion), and inferior frontal gyrus were consistently lower in patients with major depression compared to controls throughout the 6-month treatment period (
Baseline rCBF in our patients was lower than that in controls in a wide range of the frontal regions. While depressive symptoms were significantly improved at 3 months, rCBF ratios in the superior and middle frontal gyri increased. However, rCBF ratios in the middle and inferior frontal regions remained low. At 6 months, depressive symptoms continued to improve, and rCBF ratios increased in the superior frontal gyrus, middle frontal gyrus, cingulate (frontal portion), precuneus, fusiform gyrus, lingual gyrus, and cuneus. Conversely, rCBF ratios decreased in the inferior frontal gyrus, superior temporal gyrus (temporal pole), middle temporal gyrus, and superior temporal gyrus.
In the present study, rCBF increased in the left middle and superior frontal gyri after 3 months, and those on the right side increased more after 6 months. rCBF decreased in the superior temporal gyrus (temporal pole) including the amygdala after 6 months. It remained unchanged in the cingulate gyrus after 3 months but increased after 6 months. Thus, there were temporal differences in brain activity changes represented by rCBF over the course of treatment.
A period of at least 6 months is thought to be required to recover from a major depressive episode [
There have many previous studies on rCBF using SPECT in patients with major depression [
Both Arthur et al. and Mayberg et al. conducted comparative studies with healthy controls and patients with major depression using positron emission tomography (PET) [
In summary, the previous reports are inconsistent regarding some areas including the prefrontal, frontal, temporal, and parietal cortices. Among them, the temporal cortex is consistently reported to show reduced rCBF in depression, with three studies reporting lower rCBF in patients [
Davies at al. conducted a SPECT study with 99mTc-HMPAO that assessed the effect of treatment on rCBF in patients with major depression [
At the start of treatment, the left and right superior temporal gyrus (temporal pole) had low rCBF in the patient group (
In the present study, the different brain areas of depressed patients demonstrated two different patterns of blood flow change during recovery from depression. In the superior and middle frontal gyri and cingulate, blood flow increased, while it decreased in the superior temporal gyrus and temporal pole including the amygdala (
Previous brain imaging studies on depression can be summarized in that there were two common findings after successful treatment: 1) increased metabolism in the DLPFC and 2) decreased metabolism in the amygdala [
In the present study, areas in which higher rCBF was observed in patients compared to controls at 3 months included the superior temporal gyrus, inferior temporal gyrus, middle temporal gyrus, middle occipital gyrus, and fusiform gyrus. At 6 months, rCBF increased more in these areas (
The mean ages of the control and patient groups were 31.5 ± 12.8 and 46.3 ± 13.2 years, respectively, which were significantly different. Therefore, the effect of age is considered a potential problem. The literature contains several reports on the influence of age on CBF flow in healthy adults. Ances et al. [
Nagafusa et al. assessed the effect of age on rCBF in patients with depression using SPECT imaging [
Actually, Terada et al [
The following points should be considered when interpreting the present results. The number of patients was limited, and the control group was significantly more educated than the patient group. Frontal lobe function is reported to have a general correlation with years of education [
Our results showed increased blood flow in the superior and middle frontal gyri and middle temporal gyrus and decreased blood flow in the superior temporal gyrus at 3 months, as well as decreased blood flow in the temporal pole including the amygdala at 6 months after initiation of treatment for major depressive disorder. This is the first study to report these three findings in a single group of subjects.
Our results confirm that rCBF is lower in the frontal lobe and temporal pole of patients with major depression as compared to the controls prior to treatment. After treatment initiation, rCBF of the posterior temporal lobe in patients increased to a higher level than that observed in control, while rCBF of the temporal pole was further decreased in patients. The patients’ rCBF changes are thought to reflect functional improvement in cognition involving the frontal lobe and social cognition mediated by the temporal lobe. The decrease in patients’ temporal lobe rCBF may be due to less anxiety or discomfort in the course of treatment; thus, rCBF of the temporal pole including the amygdala, which plays a major role in controlling emotion, is lowered. By taking serial rCBF measurements at fixed times following the initiation of treatment for major depressive disorder, we provide the first evidence that there are temporal and regional differences in rCBF recovery in major depression. Thus, the extent of recovery from depression can be objectively monitored, and it may be possible to obtain objective data for antidepressant dose reduction and discontinuation.
Miyashita, N., Ishikawa, H., Itagaki, S., Takanashi1, Y., Okano, T., Mashiko, H., Shishido, H. and Niwa, S.-I. (2017) Longitudinal rCBF Changes Measured with SPECT in Patients with Depression Undergoing Treatment. Open Journal of Psychiatry, 7, 147-161. https://doi.org/10.4236/ojpsych.2017.73014